title: Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response.
abstract: The molecular basis of different outcomes in pediatric acute lymphoblastic leukemia (ALL) remains poorly understood. We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionizing radiation (IR)-induced DNA double-strand breaks in 74 pediatric patients with ALL. We found an apoptosis-resistant response in 36% of patients characterized by failure to cleave caspase-3, -7, -9, and PARP1 by 24 hours after IR and an apoptosis-sensitive response with the cleavage of the same substrates in the remaining 64% of leukemias. Resistance to IR in vitro was associated with poor early blast clearance at day 7 or 15 and persistent minimal residual disease (MRD) at day 28 of induction treatment. Global gene expression profiling revealed abnormal up-regulation of multiple prosurvival pathways in response to IR in apoptosis-resistant leukemias and differential posttranscriptional activation of the PI3-Akt pathway was observed in representative resistant cases. Importantly, pharmacologic inhibition of selected prosurvival pathways sensitized apoptosis-resistant ALL cells to IR in vitro. We suggest that abnormal prosurvival responses to DNA damage provide one of the mechanisms of primary resistance in ALL, and that they should be considered as therapeutic targets in children with aggressive disease.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, Birmingham University, Vincent Drive, Edgbaston, Birmingham, UK.
authors.forename: Eliot
authors.initials: E
authors.lastname: Marston
authors.forename: Victoria
authors.initials: V
authors.lastname: Weston
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jesson
authors.forename: Esther
authors.initials: E
authors.lastname: Maina
authors.forename: Carmel
authors.initials: C
authors.lastname: McConville
authors.forename: Angelo
authors.initials: A
authors.lastname: Agathanggelou
authors.forename: Anna
authors.initials: A
authors.lastname: Skowronska
authors.forename: Katie
authors.initials: K
authors.lastname: Mapp
authors.forename: Katrin
authors.initials: K
authors.lastname: Sameith
authors.forename: Judith E
authors.initials: JE
authors.lastname: Powell
authors.forename: Sarah
authors.initials: S
authors.lastname: Lawson
authors.forename: Pamela
authors.initials: P
authors.lastname: Kearns
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani
authors.forename: Malcolm
authors.initials: M
authors.lastname: Taylor
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D053903:DNA Breaks, Double-Stranded; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D066298:In Vitro Techniques; D018365:Neoplasm, Residual / Q000235:genetics / Q000473:pathology / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction
chemical_list: C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9